ARTICLE IN PRESS

THE JOURNAL OF PEDIATRICS • www.jpeds.com ORIGINAL

ARTICLES
Preschool Neurodevelopmental Outcomes in Children with
Congenital Heart Disease
Cheryl L. Brosig, PhD1,2, Laurel Bear, MD1,2, Sydney Allen, MPH1, Raymond G. Hoffmann, PhD1, Amy Pan, PhD1,
Michele Frommelt, MD1,2, and Kathleen A. Mussatto, PhD, RN1,2

Objective To describe preschool neurodevelopmental outcomes of children with complex congenital heart disease
(CHD), who were evaluated as part of a longitudinal cardiac neurodevelopmental follow-up program, as recom-
mended by the American Heart Association and the American Academy of Pediatrics, and identify predictors of
neurodevelopmental outcomes in these children.
Study design Children with CHD meeting the American Heart Association/American Academy of Pediatrics high-
risk criteria for neurodevelopmental delay were evaluated at 4-5 years of age. Testing included standardized neu-
ropsychological measures. Parents completed measures of child functioning. Scores were compared by group (single
ventricle [1V]; 2 ventricles [2V]; CHD plus known genetic condition) to test norms and classified as: normal (within
1 SD of mean); at risk (1-2 SD from mean); and impaired (>2 SD from mean).
Results Data on 102 patients were analyzed. Neurodevelopmental scores did not differ based on cardiac anatomy (1V
vs 2V); both groups scored lower than norms on fine motor and adaptive behavior skills, but were within 1 SD of norms.
Patients with genetic conditions scored significantly worse than 1V and 2V groups and test norms on most measures.
Conclusions Children with CHD and genetic conditions are at greatest neurodevelopmental risk. Deficits in chil-
dren with CHD without genetic conditions were mild and may not be detected without formal longitudinal testing.
Parents and providers need additional education regarding the importance of developmental follow-up for children
with CHD. (J Pediatr 2017;■■:■■-■■).

C
hildren with congenital heart disease (CHD) are at higher risk for neurodevelopmental problems than healthy chil-
dren, across all time points in development, from infancy through adolescence.1 Although IQ is often in the low average/
average range, a characteristic pattern of mild deficits in multiple other domains, including motor and visual spatial
skills, adaptive behavior, executive functioning, language, and social cognition, is common, and found in children with a wide
range of CHD diagnoses.2-7 Deficits are thought to be related to a number of factors including altered prenatal brain maturation,8
comorbid genetic conditions,9,10 perioperative and postoperative events,11 socioeconomic status,12 and parenting style.13 As a
result of these deficits, children with CHD are more likely than healthy children to require special education services,14 result-
ing in a significant impact on them, their families and society.15
To promote early detection of delays and optimize outcomes, the American Heart Association (AHA) and the American Academy
of Pediatrics (AAP) now recommend systematic evaluation of development in children with CHD throughout childhood.1 Cardiac
centers have begun to incorporate developmental follow-up programs as part of routine cardiac care.16,17 We have previously
reported developmental outcomes of children who were evaluated in our longitudinal developmental follow-up program over
the first 3 years of life and found that 46% of patients were delayed in at least 1 domain (cognitive, language, or motor skills);
feeding difficulty and medical and genetic comorbidities increased risk for delays.10,18 The aim of this study was to summarize
and identify predictors of neurodevelopmental outcomes for preschoolers who were seen as part of a longitudinal develop-
mental evaluation program for children with CHD.

Methods
Children with CHD believed to be at high risk for developmental delay as defined
by the AHA/AAP guidelines,1 were recruited from the Herma Heart Center
From the 1Department of Pediatrics, Medical College of
Wisconsin, Milwaukee, WI; and 2Herma Heart Center,
Children’s Hospital of Wisconsin, Milwaukee, WI
1V Single ventricle Supported in part by the National Center for Research
2V Two ventricles Resources and the National Center for Advancing
Translational Sciences, National Institutes of Health (NIH;
AAP American Academy of Pediatrics 8UL1TR000055). Its contents are solely the responsibility
AHA American Heart Association of the authors and do not necessarily represent the official
CPB Cardiopulmonary bypass views of the NIH. The authors declare no conflicts of
interest.
DHCA Deep hypothermic circulatory arrest
LOS Length of stay 0022-3476/$ - see front matter. © 2016 Elsevier Inc. All rights
WPPSI Wechsler Preschool and Primary Scales of Intelligence reserved.
http://dx.doi.org10.1016/j.jpeds.2016.12.044

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Developmental Follow-up Clinic at Children’s Hospital of Wis-
consin. Eligibility criteria and operation of the Herma Heart
Center Developmental Follow-Up Clinic have been previ-
ously described.10,16,18 Children were deemed to be at high risk
for developmental delay and eligible for the clinic if they
had any cardiac surgery as a neonate, surgery using cardio-
pulmonary bypass (CPB) in the first year of life, a cardiac defect
resulting in cyanosis, or other comorbid conditions or com-
plications such as prematurity, genetic syndromes, seizures, or
cardiac arrest that placed them at higher risk for delay. Genetic
testing was used to confirm a diagnosis when a genetic syn-
drome was suspected, but all patients did not routinely undergo
genetic testing. All families whose children met the AHA/
AAP high risk for delay criteria were contacted by letter and
subsequently called to schedule a preschool evaluation. Chil-
dren were seen for neurodevelopmental testing within the car-
diology clinic; appointments lasted approximately 2-3 hours.
Parents provided informed consent to have their child’s data
included in a databank approved by the Institutional Review
Board at Children’s Hospital of Wisconsin. No subjects were
excluded based on race or other coexisting medical or genetic
condition. Only children who spoke English were included, as
tests were administered in English.
Children completed a variety of neurodevelopmental mea-
sures that were selected based on developmental challenges that
are commonly seen in children with CHD. In addition, parents
completed several measures of child functioning and behav-
ior. All measures are validated and have normative values based
on a healthy population. New editions of some measures were
published during the 4 years in which evaluations were com-
pleted; the testing protocol was updated to include the most
current version of all measures at the time of assessment.
The full scale IQ score from the Wechsler Preschool and
Primary Scale of Intelligence (WPPSI), Third or Fourth
Edition19,20 (mean: 100 ± 15) was used as a measure of cogni-
tive functioning. The WPPSI-Fourth Edition full scale IQ score
correlates .86 with the WPPSI-Third Edition full scale IQ score.
The Letter-Word Identification, Applied Problems, and Spell-
ing subtests of the Woodcock Johnson III Tests of Achievement21
were used to assess prereading, premath, and prespelling skills,
respectively (mean: 100 ± 15). The Developmental Test of Visual
Motor Integration, Sixth Edition22 was used to assess visual
motor integration ability (mean: 100 ± 15). The Pegboard
subtest of the Wide Range Assessment of Visual Motor Abilities23
was used to assess fine motor skills (mean: 100 ± 15). The
General Communication Composite score of the Children’s
Communication Checklist-2 (completed by parent)24 was used
as a measure of language skills (mean: 100 ± 15). The General
Adaptive Composite score of the Adaptive Behavior Assess-
ment System-Second Edition (completed by parent)25 was used
as a measure of adaptive behavior (mean: 100 ± 15). The Global
Executive Composite score of the Behavior Rating Inventory
of Executive Function-Preschool Version (completed by
parent)26 was used as a measure of executive functioning (mean
T score: 50 ± 10; higher scores indicate more problems). The
Total score of the Conners’ Parent Rating Scale-Revised-
Short Form (completed by parent)27 was used as a measure of
2 Brosig et al
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Volume ■■
attention problems (mean T score: 50 ± 10; higher scores in-
dicate more problems). The Total Problems score of the Child
Behavior Checklist (completed by parent)28 was used as a
measure of child behavior problems (mean T scores: 50 ± 10;
higher scores indicate more problems). The Total score of the
Social Responsiveness Scale, First or Second Edition (com-
pleted by parent)29,30 was used as a measure of child social prob-
lems (mean T scores: 50 ± 10; higher scores indicate more
problems). The Total score is comparable across versions of
this measure, as items are exactly the same. The second edition
of this measure allows for administration across a wider age
range, and 1 subscale name was changed.
For children who were too developmentally impaired to com-
plete a task (n = 10), the lowest possible score for that test was
assigned. Children who did not complete a task for other
reasons (separation anxiety, n = 1; distractibility, n = 1; lan-
guage delay, n = 1; fatigue, n = 4; oppositional behavior, n = 7)
were excluded from analysis for tasks they did not complete.
Statistical Analyses
Sample characteristics and clinical variables are presented as
medians with IQR (25th percentile-75th percentile) for con-
tinuous data and frequencies (%) for categorical data.
Neurodevelopmental test scores were converted to standard z
scores based on test norm means/SDs and compared with the
population mean using a Wilcoxon signed rank test. Convert-
ing neurodevelopmental test scores to standard z scores, a
common metric, allowed for comparison of scores across mea-
sures, as not all neurodevelopmental tests have the same scales.
To adjust for multiple comparisons, a step-down Bonferroni
procedure was used because it is less conservative than the
Bonferroni in controlling for the family of hypotheses error
rate.31 To perform this adjustment, raw P value needs to be a
number. Therefore, a P value of <.0001 was treated as .0001.
Scores were classified as: normal (within 1 SD of test mean);
at risk (1-2 SDs from test mean); or impaired (>2 SDs from
test mean). A 1-sample proportion test was used to examine
whether the observed percentages were different from the ex-
pected percentages for impaired (2.5%) and at risk (13.5%)
categories. A Kruskal-Wallis test or Mann-Whitney-Wilcoxon
test was used to compare test scores by group (single ven-
tricle [1V] without genetic condition; 2 ventricles [2V] without
genetic condition; CHD with genetic condition). A Cochran-
Armitage trend exact test was used to examine the trend in pro-
portions of the number of domains that fell in the normal,
at risk, or impaired range for the genetic vs 1V and 2V
nongenetic groups. Univariable and multivariable logistic re-
gression analyses were used to assess the impact of patient and
clinical factors on binary neurodevelopmental test scores (at
risk/impaired vs normal). Predictors with P value of < .1 from
the univariate analyses were included in the multivariable lo-
gistic regression models (1 model for each neurodevelopmental
test) using a forward selection method. The following vari-
ables were included as predictors based on our previous
findings and a review of the literature: sex, race (White, non-
Hispanic, vs others), maternal education (completed beyond
high school vs completed high school or less), prenatal
2017 ORIGINAL ARTICLES

diagnosis, cardiac anatomy (1V vs 2V), comorbidities (none

Table I. Sample demographics (n = 102)
vs other medical vs genetic), age at first cardiac surgery, cu-
mulative hospital length of stay (LOS), cumulative CPB time, Demographics n (%)
cumulative deep hypothermic circulatory arrest (DHCA) time, Sex: male 64 (63)
history of early intervention (age 0-3 years). Statistical sig- Race/ethnicity
White, non-Hispanic 72 (71)
nificance in the final model was defined as P value of < .05. Hispanic 13 (13)
All statistical analyses were performed using SAS v 9.4 (SAS Black 8 (8)
Institute, Cary, North Carolina) software. Other 9 (9)
Maternal education
Post-high school 80 (78)
Results High school or less 16 (16)
Missing 6 (6)
Family constellation
From March 2011 through April 2015, 108 subjects with CHD Married 73 (72)
completed preschool neurodevelopmental testing as part of the Single 17 (17)
cardiac neurodevelopmental follow-up clinic. This repre- Other 11 (11)
Missing 1 (<1)
sented 28% of the potentially eligible population. Of those who Prenatal diagnosis: yes 54 (53)
did not attend the clinic, 212 (80%) did not respond to letters Premature (GA <37 wk) 18 (18)
or phone calls, so the reason they did not participate is Anatomy
2V 68 (67)
unknown. Participants were compared with nonparticipants 1V 34 (33)
on demographic and treatment characteristics. There were no Comorbidities
significant differences between groups on sex, presence of None 59 (58)
Other medical 26 (25)
known genetic or noncardiac morbidity, insurance (public or Genetic 17 (17)
private) at time of surgery, history of CPB, gestational age, age
GA, gestational age.
at first cardiac operation, or total surgical LOS. When com-
pared with nonparticipants, participants were more likely to
have 1V anatomy (35% vs 24%, P = .02); were more likely to
have been seen in the 0- to 3-year-old clinic (74% vs 58%, Of these, 16 of 17 children had 2V anatomy. One subject with
P = .002); had more cardiac operations (3.8 vs 2.9, P = .01); double inlet left ventricle had Pierre Robin syndrome.
had more minutes of CPB time (286 vs 235, P = .013); and had The majority of subjects, 92 of 102 (90%) had undergone
higher maximum Society of Thoracic Surgeons-European As- at least 1 heart surgery requiring CPB; median cumulative CPB
sociation for Cardio-Thoracic Surgery Congenital Heart Surgery time (to the time of preschool evaluation) was 221 minutes
Mortality Categories (3.8 vs 3.4, P = .002). (141-362 minutes). Of the 37 subjects who had DHCA, median
Ninety-eight percent of the subjects consented to partici- cumulative DHCA time (to the time of preschool evalua-
pation in our research databank. Four patients were ex- tion) was 12 minutes (7-28 minutes). Median cumulative hos-
cluded from this analysis because their primary diagnosis was pital LOS was 46 days (24-82 days). A majority of subjects, 85
acquired cardiomyopathy, resulting in a final sample of 102 of 102 (83%), had received early intervention services (eg, physi-
subjects with structural CHD. Of these, 75 of 102 (74%) had cal, occupational or speech therapy) previously; 42 of 102 (41%)
been previously evaluated in our developmental follow-up were currently enrolled in early intervention services at the time
program before 3 years of age. All patients who had cardiac of their preschool evaluation.
surgery at less than 1 year of age were previously referred for The percentages of the subjects for the entire cohort that
early intervention services. Characteristics of the sample are fell within the normal (within 1SD of test norm), at risk (1-2
presented in Table I. Median gestational age at birth was 39 SD from test norm) and impaired (>2 SD from test norm)
weeks (37-40 weeks). Median age at assessment was 4.5 years ranges are illustrated in Figure 1 (available at www.jpeds.com).
(4.3-4.7 years). Anatomy was classified according to the child’s In a normal distribution, 84% of a given sample should fall
diagnosis at birth. Thirty-three percent of the subjects had within the normal or above normal range, 13.5% within the
anatomy that required surgical palliation resulting in a func- at risk range, and approximately 2.5% within the impaired
tional single ventricle (list of primary cardiac diagnoses in range. Assuming a normal distribution, this cohort of chil-
Table II; available at www.jpeds.com). Twenty-five percent dren with CHD had more scores in the impaired range for all
(n = 26) of the subjects had a known medical comorbidity, in domains except parent-reported behavior problems and more
addition to their CHD, involving the following systems: airway scores in the at risk range for fine motor skills than would be
(n = 10), gastrointestinal/genitourinary (n = 5), hearing (n = 3), expected (all adjusted P < .05).
neurologic (n = 3), chronic lung disease (n = 2), multisystem Child neurodevelopmental scores and parent rating scale
(n = 2), and orthopedic (n = 1). Seventeen percent (n = 17) of results are presented in Table III. To address concerns that scores
the subjects had a diagnosed genetic condition (confirmed by for the patients with known genetic conditions would skew the
genetic testing): trisomy 21 (n = 7); 22q11 deletion (n = 3); chro- results for the entire cohort, scores were compared with test
mosomal deletion (n = 3); Turner syndrome (n = 2); VACTERL norms based on patient diagnostic group (1V without genetic
syndrome (vertebral, anal, cardiac, tracheo-esophageal, renal, condition, 2V without genetic condition, or CHD with genetic
and limb defects) (n = 1); and Pierre Robin syndrome (n = 1). condition). Scores for each diagnostic group were also
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Table III. Child completed neurodevelopmental measures and parent rating scale results
Standardized median z Raw P (z score Step-down
Median (IQR: 25th-75th (IQR: 25th-75th percentile) compared Bonferroni
Tests Domains percentile) for cases for cases with 0) adjusted P
WPPSI-III/IV IQ* Cognitive 1V 97.0 (80.0-105.0) −0.2 (−1.3 to 0.3) .066 .59
2V 102.0 (87.5-110.5) 0.1 (−0.8 to 0.7) .90 >0.99
Genetic 68.00 (40.0-79.0) −2.1 (−4.0 to −1.4) .001 .01
WJTA-III Letter-Word Pre-reading 1V 104.0 (90.0-112.0) 0.3 (−0.7 to 0.8) .56 >.99
Identification* 2V 104.0 (91.0-114.0) 0.3 (-0.6 to 0.9) .13 .78
Genetic 79.0 (40.0-106.0) −1.4 (−4.0 to 0.4) .024 .10
WJTA-III Applied Pre-math 1V 106.0 (94.0-118.0) 0.4 (−0.4 to 1.2) .34 >.99
Problems* 2V 109.0 (98.0-117.0) 0.6 (−0.1 to 1.1) .006 .06
Genetic 81.0 (40.0-94.0) −1.3 (−4.0 to −0.4) .007 .04
WJTA-III Spelling* Pre-spelling 1V 98.0 (86.0-110.0) −0.1 (−0.9 to 0.7) .53 >.99
2V 102.0 (87.0-111.0) 0.1 (−0.9 to 0.7) .88 >.99
Genetic 61.0 (40.0-92.0) −2.6 (-4.0 to −0.5) .003 .02
VMI* Visual motor 1V 95.0 (90.0-101.0) −0.3 (-0.7 to 0.1) .023 .23
2V 98.5 (93.0-106.5) −0.1 (−0.5 to 0.4) .31 >.99
Genetic 87.0 (66.0-92.0) −0.9 (−2.3 to −0.5) .001 .01
WRAVMA* Fine motor 1V 88.0 (80.0-100.0) −0.8 (−1.3 to 0.0) .0006 .007
2V 93.0 (83.0-101.5) −0.5 (−1.1 to 0.1) .0001 .001
Genetic 63.0 (45.0-76.0) −2.5 (−3.7 to −1.6) <.0001 .001
ABAS-II* Adaptive behavior 1V 88.0 (79.0-104.0) −0.8 (−1.4 to 0.3) .003 .033
2V 94.0 (77.0-101.0) −0.4 (−1.5 to 0.1) .0006 .007
Genetic 66.0 (60.0-90.0) −2.3 (−2.7 to −0.7) .0002 .002
BRIEF-P† Executive functioning 1V 50.5 (39.0-65.0) 0.1 (−1.1 to 1.5) .50 >.99
2V 48.0 (39.0-57.0) −0.2 (−1.1 to 0.7) .66 >.99
Genetic 56.5 (46.0-69.5) 0.7 (−0.4 to 2.0) .81 >.99
CPRS† Attention problems 1V 50.0 (43.0-64.0) 0.0 (−0.7 to 1.4) .28 >.99
2V 54.0 (44.0-64.0) 0.4 (−0.6 to 1.4) .06 .48
Genetic 53.0 (47.0-79.0) 0.3 (−0.3 to 2.9) .16 .48
CBCL† Behavior problems 1V 49.0 (38.5-58.5) −0.1 (−1.2 to 0.9) .54 >.99
2V 46.0 (39.5-56.0) −0.4 (−1.1 to 0.6) .10 .70
Genetic 50.0 (45.0-56.0) 0.0 (−0.5 to 0.6) >.999 >.99
SRS/SRS-2† Social problems 1V 51.0 (43.0-61.0) 0.1 (−0.7 to 1.1) .21 >.99
2V 50.5 (45.0-58.0) 0.1 (−0.5 to 0.8) .40 >.99
Genetic 59.5 (54.0-66.0) 1.0 (0.4 to 1.6) .0039 .03
CCC-2* Language 1V 102.0 (86.0-115.0) 0.1 (−0.9 to 1.0) .93 >.99
2V 109.0 (96.5-116.0) 0.6 (−0.2 to 1.1) .018 .16
Genetic 72.0 (40.0-89.0) −1.9 (-4.0 to −0.7) .0037 .03

ABAS-II, Adaptive Behavior Assessment System, Second Edition; BRIEF-P, Behavior Rating Inventory of Executive Function-Preschool; CBCL, Child Behavior Checklist; CCC-2, Children's Commu-
nication Checklist, Second Edition; CPRS, Conners' Parent Rating Scales; SRS/SRS-2, Social Responsiveness Scale, First or Second Edition; VMI, Visual Motor Integration; WJTA-III, Woodcock Johnson
Tests of Achievement-Third Edition; WPPSI-III/IV, Wechsler Preschool and Primary Scales of Intelligence, Third or Fourth Edition; WRAVMA, Wide Range Assessment of Visual Motor Abilities.
Bold P values indicate statistically significant.
*Test mean/SD 100 ± 15; higher scores indicate better functioning.
†Test mean/SD 50 ± 10; higher scores indicate worse functioning.

compared with each other. Children with 1V or 2V anatomy
without genetic conditions scored lower than test norms on
fine motor and adaptive behavior skills (adjusted P < .05). Chil-
dren with CHD and genetic conditions scored lower than
test norms and lower than children with 1V anatomy
without genetic conditions on most child completed
neurodevelopmental measures; they also scored lower on adap-
tive behavior skills and had higher rates of parent-reported
social problems (adjusted P < .05). Children with CHD and
genetic conditions scored lower than children with 2V anatomy
without genetic conditions on IQ, premath, and fine motor
skills (adjusted P < .05). No significant differences in
neurodevelopmental scores were found between children with
1V vs 2V anatomy without genetic conditions.
Children with 1V anatomy and 2V anatomy without genetic
conditions were combined into 1 group and compared with
children with CHD and genetic conditions on the percent-
age of children who fell into the following categories: (1) no
4 Brosig et al
domain scores in the at risk/impaired range (ie, all scores within
the normal range); (2) 1 domain score in the at risk range;
(3) ≥ 2 domain scores in the at risk range; or (4) ≥ 1 domain
scores in the impaired range (Figure 2). Children with CHD
without genetic conditions were less likely than children with
CHD and genetic conditions to have ≥1 domain score in the
impaired range (P = .011).
Logistic regression was performed on the dichotomized
neurodevelopmental test scores (at risk/impaired vs normal)
for each neurodevelopmental test. The significant predictors
of child neurodevelopmental outcomes in the multivariable
models are presented in Table IV. An OR >1 represented an
increased likelihood of having an “at risk/impaired” score. Pres-
ence of a genetic or other medical condition was associated
with worse neurodevelopmental outcomes in most domains.
Non-white race or Hispanic ethnicity was associated with worse
outcomes in prereading, premath, visual motor, adaptive be-
havior, and language skills. Male sex was associated with worse

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2017
Figure 2. Number of domains at risk or impaired by group (1V/
2V without genetic condition vs CHD with genetic condition).
outcomes in prespelling and fine motor skills. A longer cu-
mulative hospital LOS was associated with worse outcomes in
fine motor skills. Of note, maternal education, prenatal diag-
nosis, cardiac anatomy, age at first cardiac surgery, or minutes
of CPB/DHCA were not significantly associated with any
neurodevelopmental domains. None of the predictors in the
regression model were associated with executive function-
ing, attention, behavior, or social skills.
Discussion
In this cohort of preschool-age patients who underwent
neurodevelopmental evaluation as part of a clinical follow-
up program, findings indicate that most children with CHD
without comorbid genetic conditions do not have severe delays.
However, 50% of the children with CHD without known
genetic conditions had multiple scores in the at risk range or
at least 1 score in the impaired range, with adaptive behavior
and fine motor skills being particular areas of concern.
Not surprisingly, children with a comorbid genetic condi-
tion had worse neurodevelopmental outcomes, which is
consistent with previous findings.1,10,32 Although many studies
have excluded children with CHD and comorbid genetic
conditions,2,3,33 children with CHD and genetic conditions
Table IV. Significant predictors (P < .05) of at risk/impaired neurodevelopmental outcomes in multivariable regres-
sion models
Cognitive Prereading Premath
Male vs female
White, 0.3 (.08, 0.92) 0.2 (.06, 0.64)
non-Hispanic
vs others
Genetic condition 15.6 (3.55, 68.16) 12.2 (2.85, 52.31) 9.4 (2.14, 40.98) 11.3 (2.63, 48.50) 6.9 (1.75, 26.88) 33.2 (5.46, 201.96)
vs none
Other medical 4.7 (1.59, 13.69) 1.3 (0.27, 5.75)
condition
vs none
Hospital LOS*
*Cumulative to time of preschool assessment.
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ORIGINAL ARTICLES
represent at least 20% of the CHD population, and this number
is likely an underestimate, as not all children with CHD undergo
formal genetic testing.10 Children with CHD and comorbid
genetic conditions meet the AHA/AAP1 criteria regarding which
children should be referred for serial neurodevelopmental as-
sessment. Therefore, we believed that it was important to
include these children in our results.10,16
Of note, neurodevelopmental outcomes did not differ based
on cardiac anatomy (1V without genetic condition vs 2V
without genetic condition), which is consistent with previ-
ous research on preschool neurodevelopmental outcomes in
CHD.34 In contrast to the current preschool findings, re-
search conducted with adolescents with CHD found worse ex-
ecutive functioning in subjects with single-ventricle anatomy
compared with biventricular groups. 2 It is possible that
neurodevelopmental risks between 1V and 2V groups widen
over the course of development, as societal demands for in-
dependent problem solving and executive functioning skills
increase.
Presence of a comorbid medical or genetic condition was
the strongest predictor of at risk/impaired neurodevelopmental
outcomes across domains. In addition, minority race, male
sex, and cumulative hospital LOS predicted adverse
neurodevelopmental outcomes in some domains. Early patient
or treatment characteristics, such as prenatal diagnosis, age
at first cardiac surgery, or CPB/DHCA time, did not predict
preschool neurodevelopmental outcomes. It appears that early
treatment factors have less impact on development the farther
the child is out from surgery; whereas intrinsic factors such
as ongoing medical/genetic problems (which may contribute
to longer hospital LOS) and minority race (which may be a
proxy for socioeconomic disadvantage), may have more impact
on development over time. It was surprising that males did
worse on fine motor and prespelling skills, as sex was not
found to be a risk factor in our previous studies.10,16,18 However,
findings of the current study are consistent with recent reports
that have shown similar differences by sex in motor and
writing skills in healthy children.35,36 It is interesting to note
that no factors examined in the present study predicted prob-
lems with executive functioning, attention, or behavior, deficits
that are frequently seen in older children with CHD.2 In the
Prespelling Visual motor Fine motor Adaptive behavior Language
OR (95% CI)
3.7 (1.04, 13.16) 6.7 (1.69, 26.15)
0.2 (.07, 0.69) 0.3 (0.10, 0.87) 0.3 (0.10, 0.97)
6.3 (1.61, 25.05) 7.8 (2.10, 29.04)
2.2 (0.69, 7.13) 2.5 (0.66, 9.91) 1.3 (0.42, 3.97) 1.9 (0.66, 5.79) 1.1 (0.28, 4.10)
1.01 (1.00, 1.02)
5
THE JOURNAL OF PEDIATRICS • www.jpeds.com
present study, executive functioning, attention, and behavior
were assessed exclusively via parent questionnaires, which
may have influenced the results. Nonetheless, findings suggest
that there is no clear profile of factors that consistently pre-
dicts all areas of development in patients with CHD over
time.
There are some important limitations to the current study.
Results are based on a single center experience, and not all pa-
tients who were eligible for the clinic participated; thus, find-
ings may not be generalizable to the CHD population as a
whole. It is possible that results represent a “best-case sce-
nario,” as the majority of the sample (74%) had been previ-
ously evaluated in our neurodevelopmental follow-up program,
and the majority (83%) had received early intervention
services. Thus, results may underestimate the level of
neurodevelopmental deficits in this age group, particularly
for patients with CHD who are not receiving systematic
neurodevelopmental evaluation or early intervention ser-
vices. As evaluations were conducted as part of a clinical
program, and not as part of a research study, it was not pos-
sible for us to recruit a healthy control sample, which is an ad-
ditional limitation. As patients were evaluated in the clinic over
a period of several years, it is possible that outcomes could have
been influenced by changes in surgical or clinical manage-
ment; however, this is unlikely, as our comprehensive
neuroprotective strategy remained stable throughout the course
of this study. Finally, although multiple neurodevelopmental
domains were assessed as part of the preschool evaluation, it
is not known whether preschool neurodevelopmental out-
comes will predict neurodevelopmental outcomes at school-
age and beyond.
Cardiology providers, primary care providers/pediatricians,
and other members of the child’s medical team should counsel
parents that formal developmental testing can identify the
child’s strengths and weaknesses, which often change as the
child gets older. The information obtained can also help parents
advocate for their child’s unique needs as they enter the school
system. As more cardiac centers incorporate developmental
follow-up programs into their clinical care,17 quality improve-
ment initiatives designed to increase family participation will
be beneficial. ■
We acknowledge the support of Mara Koffarnus, Kristen Andersen, and
Katie Wilde for patient scheduling and data management support. We
thank the children and parents who attended developmental follow-
up and were willing to participate in this research.
Submitted for publication Sep 2, 2016; last revision received Nov 1, 2016;
accepted Dec 14, 2016
Reprint requests: Cheryl L. Brosig, PhD, Department of Pediatrics, Medical
College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
E-mail: cbrosig@chw.org
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THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

Figure 1. Percentage of patients in the normal, at risk, and impaired ranges on neurodevelopmental measures.

Table II. Primary cardiac diagnoses

2V congenital heart defects n = 68
Aortic arch hypoplasia or coarctation 12
Atrioventricular septal defect 8
Ventricular septal defect 8
Transposition of the great arteries with intact ventricular septum 6
Aortic valve stenosis 4
Pulmonary atresia + ventricular septal defect 4
Double outlet right ventricle 3
Interrupted aortic arch 3
Tetralogy of Fallot 3
Total anomalous pulmonary venous connection 3
Transposition of the great arteries with ventricular septal defect 3
Atrioventricular septal defect with tetralogy of Fallot 2
Pulmonary atresia with intact ventricular septal septum 2
Truncus arteriosus 2
Ebstein malformation of tricuspid valve 1
Double aortic arch 1
Mitral valve stenosis 1
Pulmonary valve stenosis 1
Congenitally corrected transposition of the great arteries with ventricular septal defect 1

1V congenital heart defects n = 34

Hypoplastic left heart syndrome 20
Double inlet left ventricle 6
Double outlet right ventricle 3
Pulmonary atresia + intact ventricular septum 3
Congenitally corrected transposition of the great arteries 1
Tricuspid atresia 1

7.e1 Brosig et al

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